The <I>WT1</I> gene was isolated by positional cloning as a candidate gene implicated to predisposition to the paediatric kidney cancer Wilms' tumour. Because of its early onset and histological resemblance to immature kidneys, Wilms' tumour was thought to arise from an aberration in the normal developmental pathway. From the amino acid sequence, <I>WT1</I> was predicted to be a transcription factor with an N-terminal proline/glutamine rich transregulatory domain and four C-terminal <I>TFIIIA</I>-like zinc fingers. Two alternative splices have been found in the transcript, resulting in the insertion of 17aa or 3aa (KTS). Functional analysis has shown that <I>WT1</I> is capable of sequence specific DNA binding and of regulating transcription. Analysis of <I>WT1</I> mRNA in the developing embryo has shown a pattern of expression consistent with an important role in nephrogenesis, specifically an involvement in mesenchymal-epithelial cell transition. <I>WT1</I> analysis in Wilms' tumours revealed that both functional copies are lost in about 10% of sporadic Wilms' tumours. This confirmed the role of <I>WT1</I> as a tumour suppressor gene in at least some cases, (following Knudson's two hit hypothesis for tumorigenesis). Predisposition to Wilms' tumour can also be associated with developmental abnormalities, including genitourinary malformations. Expression of <I>WT1</I> is seen in the earliest stages of gonad development and constitutionally heterozygous mutations in <I>WT1</I> are frequently associated with genitourinary abnormalities. The most sever abnormalities, in Denys-Drash syndrome, have been linked to heterozygous constitutional <I>WT1</I> missense mutations in the zinc fingers. The cloning of the mouse <I>WT1</I> gene revealed a very high level of similarity to the human gene, as well as a very similar pattern of expression during development.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:653309 |
| Date | January 1994 |
| Creators | Kent, Gillian R. L. |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/15155 |
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